DESCRIPTION OF OVERALL CENTER (provided by applicant): The proposed Silvio O. Conte Center for Neuroscience of Depression will focus on understanding the neurobiological mechanism of depression. We will use the naturally occurring lesions in the elderly depressed as a model. We will use a lesion approach to study the mood circuit and affect regulation. A total of 5 projects are proposed. The first examines localization of lesions, structural changes in critical regions subserving the circuit and alterations in the white matter tracts relevant to the circuit. The second project uses post mortem cell counting and glial volume assessment to assess changes in the relevant region. The third project uses cognitive paradigms and functional MRI to probe the circuit. The fourth project uses transgenic and knockout mice to examine the role of norepinephrine and serotonin as it relates to the circuit. The final project is designed to assess in humans the impact of norepinephrine and serotonin depletion in remitted depressed patients with lesions to evaluate the importance of these neurotransmitters as a mechanism. Three shared resources, administrative, research, and assessment and data management/statistics are proposed to facilitate the conduct of these projects and to ensure integration at the conceptual, analytical and patient availability level, and flow to the various projects. Findings from the center should greatly enhance our understanding of the biology of depressive disorders, but may also be of help in improving the treatment of these disorders. In addition, the technological innovations developed in the context of this project are likely to be of major importance and relevant to other studies of brain function.